tbuckley/cabot-search huggingface dataset:
OS08.8.A Integrin-specific CAR T cells for the treatment of glioblastoma
Authors: D Villars, L Hänsch, M Silginer, T Weiss, M Weller, P Roth
Journal: Neuro-Oncology (2022)

Abstract Background Current standard of care for glioblastoma patients has limited therapeutic efficacy and novel innovative treatment strategies are urgently needed. One such strategy is chimeric antigen receptor (CAR) T cell therapy that has shown great success in hematological malignancies. αv integrins are overexpressed in several neoplasms and have already been used as therapeutic targets for small molecule inhibitors and antibodies, which did not cause major toxicities. Herein, we propose αv integrins as an ideal target for CAR T cell therapy in glioblastoma. Material and Methods CAR T cells targeting specific heterodimers (αvβ3, αvβ5 or αvβ8) were generated by transducing primary human T cells from healthy donors with a lentiviral vector expressing a second-generation CAR. Activity and specificity of CAR T cells was determined by co-culture assays with different glioma cells. Efficacy of CAR T cells to control tumor growth in vivo was investigated in clinically relevant orthotopic xenograft glioma mouse models. Additionally, we generated CAR T cells from T cells from a glioblastoma patient and measured their activity against the patient’s autologous tumor cells. Results All newly generated integrin-targeting CAR T cells exerted strong anti-glioma activity in vitro. Long-term and repetitive killing assays as well as cytokine-release measurements demonstrated highest activity of αvβ5 and αvβ8 integrin-specific CAR T cells. Antigen specificity of these cells was confirmed, as glioma cells with a CRISPR/Cas9-mediated knockout of the target antigen were resistant to CAR T cell-mediated cytotoxicity. Intratumoral injection of αvβ5 or αvβ8 CAR T cells significantly prolonged the survival and cured a substantial fraction of glioma-bearing mice in two different xenograft models. When used in a patient-derived setting, matched CAR T cells exerted strong anti-glioma activity. Conclusion We show strong and integrin-specific anti-glioma activity of CAR T cells developed from healthy donor T cells and glioblastoma-patient-derived T cells in vitro. αvβ5- and αvβ8-specific CAR T cells exerted the best therapeutic activity in two different xenograft glioma models in vivo. These data support the evaluation of integrin-specific CAR T cells as a therapeutic strategy in clinical neuro-oncology.
Disclosure Information
Authors: Ghazaleh Tabatabai, Modest Contribution, D Speakers
Journal: Neuro-Oncology (2022)

In order to help readers form their own judgments of potential bias in published abstracts, authors are asked to declare any competing financial interests.Contributions of up to EUR 10 000.-(Ten thousand Euros, or equivalent value in kind) per year per company are considered "Modest".Contributions above EUR 10 000.-per year are considered "Significant".
OS03.5.A Characterization of the inflammatory tumor microenvironment composition in solid cancer patients with brain metastases after progression to immune checkpoint inhibitor therapy
Authors: A M Starzer, M Kleinberger, K Feldmann, E Tomasich, T Hatziioannou, C Paiato, G Heller, J Kreminger, S Traint, A Steindl, J M Ressler, G Widhalm, B Gatterbauer, K Dieckmann, L Müllauer, M Preusser, A S Berghoff
Journal: Neuro-Oncology (2022)

Abstract Background Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms. Material and Methods Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO). Results Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p&amp;gt;0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort. Conclusion Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.
P02.10.A CRISPR/Cas9 deletion of SOX2 Regulatory Region 2 (SRR2) decreases SOX2 malignant activity in glioblastoma
Authors: A Saenz-Antoñanzas, V Moncho-Amor, A Elúa-Pinín, K Rizzoti, R Lovell-Badge, A Matheu
Journal: Neuro-Oncology (2022)

Abstract Background SOX2 is a transcription factor associated with stem cell activity in several tissues. SOX2 expression is elevated in a large proportion of cancers, such as glioblastoma (GB), the most common malignant primary brain tumor in adults. SOX2 acts as a relevant driver of GB progression and high levels are associated with the population of tumor initiating cells and poor patient outcome. Transcriptional regulation of SOX2 is complex and not fully understood. The SOX2 regulatory region 2 (SRR2) is located downstream of the SOX2 coding region and mediates SOX2 expression by the association of p21CIP1 and p27KIP1 to SRR2. In this study we dissected the role of SRR2 on SOX2 activity in GB. Material and Methods We deleted SRR2 (SRR2del) by CRISPR/Cas9 technology in U373 GB cells. We analyzed the expression of SOX2 and performed in vitro functional experiments. We accomplished rescue experiments overexpressing SOX2 in SRR2del cells and we studied the link between SOX2, p21CIP1 and p27KIP1. Finally, we carried out an in vivo carcinogenesis assay by the injection of SRR2del cells in immunodeficient mice. Results We report that the deletion of SRR2 in GB cells leads to a reduction of SOX2 expression, which was accompanied with an impairment of cell growth and proliferation as well as with a reduction of self-renewal capacity in vitro. These data reveal that SRR2 is required for SOX2 expression and that its deletion results in impaired tumorigenic capacity of GB cells. These effects correlated with an increased expression of p21CIP1 and p27KIP1 together with high levels of p53 in SRR2del cells. On the contrary, SRR2del cells presented decreased levels of stem cell markers, supporting the idea that SRR2 is necessary for the SOX2-mediated regulation of stemness pathways. Furthermore, ectopic overexpression of SOX2 in SRR2del cells restored SOX2 expression as well as proliferation and stem cell properties, indicating that the expression and the oncogenic activity of SOX2 is regulated by SRR2. Additionally, our xenograft models revealed that the lack of SRR2 impairs tumor initiation and growth in vivo. Tumors derived from SRR2del cells were significantly smaller compared to controls and exhibit low levels of SOX2, Ki67 and BMI1 but high levels of p21CIP1 and p27KIP1. Conclusion Our data confirm that the SRR2 regulates SOX2 expression and reveal that SRR2 deletion reduces SOX2 levels and halts malignant activity driven by SOX2 in GB.
P08.08.B Long-term survival and health-related quality of life in meningioma patients: a mixed-methods systematic review
Authors: S Frances, L Murray, J Wright, G Velikova, F Boele
Journal: Neuro-Oncology (2022)

Abstract Background Meningiomas account for approximately 36% of all primary brain tumours. These tumours have a relatively favourable prognosis with approximately 92% of meningioma patients surviving &amp;gt;5 years after diagnosis. Yet, patients report high disease burden and survivorship issues even years after treatment, including cognitive issues and anxiety/depression affecting health-related quality of life (HRQOL). We aimed to systematically review the literature and synthesise evidence on HRQOL in meningioma patients across long-term survival, defined as &amp;gt;2 years post diagnosis. Material and Methods Systematic literature searches were carried out using Medline, EMBASE, CINAHL, PsycINFO, and Web of Science Core Collection up to November 2021. Two independent assessors carried out screening. Any published, peer reviewed article with primary quantitative or qualitative data covering the physical, mental, and/or social aspects of HRQOL were included. Quality was assessed using the Mixed Methods Appraisal Tool, before a data-based convergent synthesis design was used to interpret findings. Results The search returned 2252 articles. Following screening 12 papers were included in the review. The majority of studies used quantitative methods, with only one study reporting mixed-methodology. Two of these were articles from the same study. Most used cross-sectional assessments (n =10) with two reporting longitudinal assessments (n = 2). Included meningioma patient samples (n=2990 in total) represented a wide range of survival lengths (range: 24 months - 10 years). HRQOL was impacted predominantly through physical and mental issues, including persevering symptoms (e.g. headaches, fatigue, vision problems) and emotional difficulties (e.g. poorer mental and general health perceptions). Returning to work proved difficult for patients due to cognitive and social deficits (e.g. issues with concentration, procrastination and isolation). Factors including age and comorbidities, but also treatment type appears to affect patients’ satisfaction with their HRQOL. Conclusion While overall prognosis following a meningioma diagnosis is good, meningioma patients’ HRQOL appears affected throughout long-term survivorship. Findings from this review could be beneficial in addressing the HRQOL and supportive-care needs of patients across long-term survivorship.
OS02.5.A Alzheimer-type neuropathological changes in glioblastoma-adjacent cortex
Authors: L Greutter, Y Miller-Michlits, S Klotz, A Miller-Michlits, T Roetzer-Pejrimovsky, B Baumann, B Kiesel, G G Kovacs, P Stepper, A Woehrer
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is an aggressive type of brain cancer that is prevalent and fatal in the elderly. Age is not only the most common risk factor for brain cancer but also for neurodegenerative diseases, and previous studies have indicated an excess risk of co-occurrence of both diseases. Here, we aim to map Alzheimer (AD)-related pathology in GBM-adjacent cortex. Material and Methods To this end, we have screened a cohort of 99 individuals with 200 tissue samples comprising tumor and adjacent cortex, including longitudinal samples in 13 patients. The samples were provided by the Division of Neuropathology and Neurochemistry, Medical University of Vienna from 2002 to 2021. Age and tumor location were abstracted from clinical data where available. All samples were stained for A-beta, tau-AT8 and NeuN using immunohistochemistry. Whole slide scans were segmented and protein deposits were quantified with QuPath. Further statistical analyses were conducted with R. Tau pathology was recorded as neurofibrillary tangles, neuropil threads, and astroglial pathology. Likewise, amyloid pathology was assessed as plaques and/or cerebral amyloid angiopathy (CAA). For both proteins, deposits were grouped into: absent, mild, moderate, and severe. Results In the total cohort, median age was 67.5 ys (range 20-92 ys), the female-to-male ratio 0.68. Overall 44.4 % (n=44/99) showed any type of A-beta and/or taupathology, which was strongly correlated with age (R=0.26, p= 0.001). Among them, 38.6 % (n=17/44) had combined pathology, while 36.4 % (n=16/44) displayed pure amyloid-beta, and 25 % (n=11/44) only tau pathology. A-beta pathology comprised plaques in 74.4 % (n=29/39) and CAA in 28.2 % (n=11/29). Consistent with the spatiotemporal evolution of AD, neurofibrillary tangle load was highest in the temporal lobe (42.9 % n=21/49), while plaque load was most prevalent in the occipital lobe (62.5 % n=5/8). This pattern was accentuated in patients above age 65, while it deviated in those below age 65. Over time, the AD-type pathology increased in 38.4 % (n=5/13) and remained stable in 53.8 % (n=7/13) of recurrent tumors. Total cell densities in tumor-infiltrated cortex ranged from 474 to 7,540 cells/mm2, being similar across all lobes. Higher cell density correlated with decreased neuronal counts (R= -0.46, p&amp;lt;0.0001) and decreased AD-load (R= -0.25, p= 0.002). Conclusion Collectively, our results establish frequent co-occurrence of Alzheimer disease neuropathological changes in the GBM-adjacent cortex. They prompt further investigation of shared pathogenic mechanisms and seek to raise awareness for synergistic effects on cognitive decline.
OS07.7.A Rate and type of recurrence of lower-grade gliomas submitted to functional neurosurgical approach: the impact of the extent of resection
Authors: L Gay, M Rossi, M Conti Nibali, T Sciortino, L Bello
Journal: Neuro-Oncology (2022)

Abstract Background In the last decade, different published studies enlightened the extent-of-resection (EOR) as an independent factor for progression-free-survival (PFS) in patients with lower-grade gliomas (LGG). Aim of this study was to evaluate the impact of resections extending beyond FLAIR MRI abnormalities (supratotal), and eventual predictive factors and characteristics of recurrences. Material and Methods We retrospectively analysed 460 patients submitted to surgery between 2007 and 2016 with a presumptive diagnosis of LGG, i.e., harbouring a mass lesion with no enhancement on contrast-administered T1-weighted MRI-sequences. All resections were performed according to functional boundaries determined by brain mapping/monitoring technique, without any patient or tumor a priori selection. The EOR was defined by analyzing pre- and post-operative volumetric FLAIR images. Results The median pre-operative tumor volume was 43,7 cm3. A supratotal resection (SPR) was achieved in 31.4%, a gross-total (GTR) in 41.1%, a subtotal (STR) in 27.5%. WHO grade II/III gliomas were diagnosed in 347 cases (319 IDH-mutant, 28 IDH-wildtype). Median follow-up was 60 months. SPR versus other EOR was associated to increased PFS (log rank test, p=.000) and malignant PFS (p=.000). Data were confirmed also after IDH status stratification. Rate of immediate and permanent post-op deficits among different EOR were comparable. Pre-op tumor volume, parietal and insular sites, eloquent location and dominant hemisphere tumors, and astrocytoma histology were associated to recurrence (p&amp;lt;.05). In 95.1% of cases recurrences were peri-cavitary. Lesions invading the corpus callosum presented minor rate of relapse; recurrences were most frequently diffuse and at distant sites. After SPR most common radiological appearance of recurrence was solid, while after GTR and STR percentages of solid and diffuse patterns were similar. Occurrence of distant recurrences, away from the resection cavity, were most associated to SPR. Conclusion Our preliminary data suggests the dramatic impact in LGG of resections extending beyond FLAIR abnormalities on PFS and malignant PFS and on the characteristics of tumor recurrence.
OS01.6.A Through the Looking Glass: CSF Proteomics for Glioma Monitoring and Response Assessment
Authors: C Riviere-Cazaux, T Burns
Journal: Neuro-Oncology (2022)

Abstract Background The development of novel glioma therapies necessitates rapid, longitudinal, and individualized feedback from each patient's tumor. Due in part to the relative inaccessibility of dynamic gliomas, little information is available regarding mechanisms of in situ therapeutic response and resistance which may be needed to iteratively develop candidate therapies and combinations thereof. To address this challenge, we are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. Material and Methods Global proteomic analysis of CSF was performed on the Somalogic platform -- an aptamer-based technology for highly sensitive and specific analyses of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria: 1) decrease with lower tumor burden as defined by tumor resection, and 2) increase with greater tumor burden as defined by recurrence in individual paired patient samples. Results Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. When queried in an independent validation cohort, the HGG proteomic signature was consistently enriched across 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. In two patients for whom CSF was available prior to and immediately after resections, proteins in the HGG signature decreased as indicated by a lower tumor burden. Interestingly, the glioma CSF proteomic signature was highly enriched for blood-associated proteins (as defined by two paired sets of CSF samples with low vs. high hemoglobin), despite these patients' samples containing little-to-no hemoglobin proteins. Conclusion Global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas has the promise to yield biomarkers which may be used to gain insights regarding glioma biology, tumor burden, and evolution throughout a patient's disease and treatment course.
OS07.8.A Prognosis in IDH-mutant glioma: the role of extent-of-resection, age and tumor grade
Authors: T van der Vaart, M M J Wijnenga, K A van Garderen, H Dubbink, P J French, M Smits, C M F Dirven, J M Kros, A P J E Vincent, M J van den Bent
Journal: Neuro-Oncology (2022)

Abstract Background Evidence suggests that smaller residual tumor volumes after initial surgery are associated with longer survival in patients with astrocytoma, IDH-mutant, grade II. For IDH-mutant glioma of higher grade but also for oligodendroglioma, IDH-mutant, and 1p/19q codeleted, the impact on survival of more residual tumor is unclear. This could be related to the limited follow-up of patients with oligodendroglioma that typically have long overall survival. We expanded a previously published series of patients increase the duration of follow-up and the spectrum of tumor grades. Material and Methods Single center observational cohort study of patients with adult-type diffuse glioma, IDH-mutant, all WHO-2021 grades, from 2003 to 2021 . Molecular characteristics were assessed by next-generation targeted sequencing. Tumor volumes were calculated by semi-automatic 3D segmentation on pre- and postoperative MRI-scans. Associations between prognostic factors and survival were assessed using univariate and multivariate Cox proportional hazards models. Results 384 patients with IDH-mutant glioma (174 oligodendroglioma, 212 astrocytoma) were followed for a median of 7 years. Median age at diagnosis was 41 years (IQR 33 - 55). Significant prognostic factors for survival were Karnofsky performance status, 1p19q-status and post-operative tumor volume. Smaller post-operative tumor volume was associated with better survival, both in astrocytoma and oligodendroglioma. Age, tumor grade and MRI-contrast enhancement were not associated with survival. Conclusion Lower residual tumor volume after first surgery is a strong prognostic factor in all IDH-mutant glioma subgroups, even in patients with very small residual tumor. Importantly, age and histological tumor grade were not significantly associated with survival. The data serves as further support for optimal initial resections of tumors suspected for IDH-mutant glioma, also in oligodendroglioma.
P01.16.B Neurocognitive outcome and seizure freedom after awake surgery of gliomas
Authors: S Reitz, M Behrens, I Lortz, N Conradi, M Rauch, K Filipski, M Voss, C Kell, M Czabanka, M Forster
Journal: Neuro-Oncology (2022)

Abstract Background Gliomas are often diagnosed due to epileptic seizures as well as neurocognitive deficits. First treatment choice for patients with gliomas in speech-related areas is awake surgery, which aims at maximizing tumor resection while preserving or improving patient’s neurological status. The present study aimed at evaluating neurocognitive functioning and occurrence of epileptic seizures in patients suffering from gliomas located in language-related areas before and after awake surgery as well as during their follow up course of disease. Material and Methods In this prospective study we included patients who underwent awake surgery for glioma in the inferior frontal gyrus, superior temporal gyrus, or anterior temporal lobe. Preoperatively, as well as in the short-term (median 4.1 months, IQR 2.1-6.0) and long-term (median 18.3 months, IQR 12.3-36.6) postoperative course, neurocognitive functioning, neurologic status, the occurrence of epileptic seizures and number of antiepileptic drugs were recorded. Results Between 09/2012 and 09/2019, a total of 27 glioma patients, aged 36.1 ± 11.8 years, were included. Tumor resection was complete in 15, subtotal in 6 and partial in 6 patients, respectively. While preoperatively impairment in at least one neurocognitive domain was found in 37.0% of patients, postoperatively, in the short-term, 36.4% of patients presented a significant deterioration in word fluency (p=0.009) and 34.8% of patients in executive functions (p=0.049). Over the long-term, scores improved to preoperative baseline levels. The number of patients with mood disturbances significantly declined from 66.7% to 34.8% after surgery (p=0.03). Regarding seizures, these were present in 18 (66.7%) patients prior to surgery. Postoperatively, 22 (81.5%) patients were treated with antiepileptic drugs with all patients presenting seizure-freedom. Conclusion In patients suffering from gliomas in eloquent areas, the combination of awake surgery, regular neurocognitive assessment - considering individual patients′ functional outcome and rehabilitation needs - and the individual adjustment of antiepileptic therapy results in excellent patient outcome in the long-term course.